Search

Abstract The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is reliably one of the largest pandemics the world has suffered in recent years. In the search for non-biological antivirals, special emphasis was placed on drug repurposing to accelerate the clinical implementation of effective drugs. The life cycle of the virus has been extensively investigated and many human targets have been identified, such as the molecular chaperone GRP78, representing a host auxiliary factor for SARS-CoV-2 entry. Here we report the inhibitor capacity of TL1228, a small molecule discovered through an in silico screening approach, which could interfere with the interaction of SARS-CoV-2 and its target cells, blocking the recognition of the GRP78 cellular receptor by the viral Spike protein. TL1228 showed in vitro the ability to reduce significantly both pseudoviral and authentic viral activity even through the reduction of GRP78/ACE2 transcript levels. Importantly, TL1228 acts in modulating expression levels of innate immunity and as inflammation markers.

Abstract IP3 receptor (IP3R)-mediated Ca2+ transfer at the mitochondria-endoplasmic reticulum (ER) contact sites (MERCS) drives mitochondrial Ca2+ uptake and oxidative metabolism and is linked to different pathologies, including Parkinson’s disease (PD). The dependence of Ca2+ transfer efficiency on the ER-mitochondria distance remains unexplored. Employing molecular rulers that stabilize ER-mitochondrial distances at 5 nm resolution, and using genetically encoded Ca2+ indicators targeting the ER lumen and the sub-mitochondrial compartments, we now show that a distance of ~20 nm is optimal for Ca2+ transfer and mitochondrial oxidative metabolism due to enrichment of IP3R at MERCS. In human iPSC-derived astrocytes from PD patients, 20 nm MERCS were specifically reduced, which correlated with a reduction of mitochondrial Ca2+ uptake. Stabilization of the ER-mitochondrial interaction at 20 nm, but not at 10 nm, fully rescued mitochondrial Ca2+ uptake in PD astrocytes. Our work determines with precision the optimal distance for Ca2+ flux between ER and mitochondria and suggests a new paradigm for fine control over mitochondrial function.

Abstract Background Some chromatinopathies may present with common clinical findings (intellectual disability, brain and limb malformation, facial dysmorphism). Furthermore, one of their cardinal shared features is growth dysregulation.We aimed to assess and deepen this resemblance in three specific conditions, namely Wiedemann-Steiner (WDSTS), Kleefstra (KLEFS1) and Coffin-Siris syndrome (CSS1), with a particular focus on possible metabolic roots. Methods Eleven patients were enrolled, three with WDSTS, five with KLEFS1 and three with CSS1, referring to Fondazione IRCCS Ca’ Granda Ospedale Maggiore, Milan, Italy. We performed both a physical examination with detailed anthropometric measurements and an evaluation of the patients’ REE (rest energy expenditure) by indirect calorimetry, comparing the results with age- and sex-matched healthy controls. Results We observed new clinical features and overlap between these conditions suggesting that different disturbances of epigenetic machinery genes can converge on a common effect, leading to overlapping clinical phenotypes. The REE was not distinguishable between the three conditions and healthy controls. Conclusions Epigenetic machinery plays an essential role both in growth regulation and in neurodevelopment; we recommend evaluating skeletal [craniovertebral junction abnormalities (CVJ) polydactyly], otolaryngological [obstructive sleep apnea syndrome (OSAs), recurrent otitis media], dental [tooth agenesis, talon cusps], and central nervous system (CNS) [olfactory bulbs and cerebellum anomalies] features. These features could be included in monitoring guidelines. Further studies are needed to deepen the knowledge about energy metabolism.

Abstract Background Silver-Russell Syndrome (SRS, MIM #180860) is a clinically and genetically heterogeneous disorder characterized by intrauterine and postnatal growth retardation; SRS is also accompanied by dysmorphic features such as triangular facial appearance, broad forehead, body asymmetry and significant feeding difficulties. The incidence is unknown but estimated at 1:30,000-100,000 live births. The diagnosis of SRS is guided by specific criteria described in the Netchine–Harbison clinical scoring system (NH-CSS). Case presentation Hereby we describe four patients with syndromic short stature in whom, despite fitting the criteria for SRS genetic analysis (and one on them even meeting the clinical criteria for SRS), molecular analysis actually diagnosed a different syndrome. Some additional features such as hypotonia, microcephaly, developmental delay and/or intellectual disability, and family history of growth failure, were actually discordant with SRS in our cohort. Conclusions The clinical resemblance of other short stature syndromes with SRS poses a risk of diagnostic failure, in particular when clinical SRS only criteria are met, allowing SRS diagnosis in the absence of a positive result of a genetic test. The presence of additional features atypical for SRS diagnosis becomes a red flag for a more extensive and thorough analysis. The signs relevant to the differential diagnosis should be valued as much as possible since a correct diagnosis of these patients is the only way to provide the appropriate care pathway, a thorough genetic counselling, prognosis definition, follow up setting, appropriate monitoring and care of possible medical problems.

Despite an established body of research characterizing how creative individuals explore their "external" world, relatively little is known about how such individuals navigate their "inner mental life", especially in unstructured contexts such as periods of awake rest. Across two studies, the present manuscript tested the hypothesis that creative individuals are more engaged with their idle thoughts and more associative in the dynamic transitions between them. Study 1 captured the real-time conscious experiences of 81 adults as they voiced aloud the content of their mind moment-by-moment across a 10-minute unconstrained baseline period. Higher originality scores on a divergent thinking task were associated with less perceived boredom, more words spoken overall, more freely moving thoughts, and more loosely-associative (as opposed to sharp) transitions during the baseline rest period. In Study 2, across 2,612 participants, those who reported higher self-rated creativity also reported less perceived boredom during the COVID-19 pandemic, a time during which many people experienced unusually extended periods of unstructured free time. Overall, these results suggest a tendency for creative individuals to be more engaged and explorative with their thoughts when task demands are relaxed, raising implications for resting state functional MRI and societal trends to devalue idle time.

This study presents an automated methodology for evaluating micro-channels fabricated using a femtosecond laser on stainless steel substrates. We utilize 3D surface topography and metrological analyses to extract geometric features and detect fabrication defects. Standardized samples were analyzed using a light interferometer, and the resulting data were processed with Principal Component Analysis (PCA) and RANSAC algorithms to derive channel characteristics, such as depth, wall taper, and surface roughness. The proposed method identifies common defects, including bumps and V-defects, which can compromise the functionality of micro-channels. The effectiveness of the approach is validated by comparisons with commercial solutions. This automated procedure aims to enhance the reliability and precision of femtosecond laser micro-milling for industrial applications. The detected defects, combined with fabrication parameters, could be ingested in an AI-based process to optimize fabrication processes.

Abstract Anisotropic transport properties have been assessed in a number of cuprate superconductors, providing evidence for a nematic state. We have recently shown that in ultra-thin YBa2Cu3O7−δ films, where nematicity is induced via strain engineering, there is a suppression of charge density wave scattering along the orthorhombic a-axis and a concomitant enhancement of strange metal behavior along the b-axis. Here we develop a microscopic model, that is based on the strong interaction between the substrate facets and the thin film, to account for the unconventional phenomenology. Based on the atomic force microscopy imaging of the substrates’ surface, the model is able to predict the absence (presence) of nematicity and the resulting transport properties in films grown on SrTiO3 (MgO) substrates. Our result paves the way to new tuning capabilities of the ground state of high-temperature superconductors by substrate engineering.

Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative diseases on a global scale. Historically, this pathology has been linked to cholinergic transmission, and despite the scarcity of effective therapies, numerous alternative processes and targets have been proposed as potential avenues for comprehending this complex illness. Nevertheless, the fundamental pathophysiological mechanisms underpinning AD remain largely enigmatic, with a growing body of evidence advocating for the significance of muscarinic receptors in modulating the brain’s capacity to adapt and generate new memories. This review summarizes the current state of the art in the field of muscarinic receptors’ involvement in AD. A specific key factor was the relationship between comorbidity and the emergence of new mechanisms.

Wood fuel from the agroforestry sector is one of the main strategies cited by the EU for reducing energetic dependance on foreign markets. Its sustainability, both economic and environmental, can be improved through the optimization of harvesting and chipping operations. This study was focused on the dynamic and energetic balance of the chipping phase carried out by a chipper operated by the power-take-off (PTO) of a medium-power tractor. Both machines were equipped with sensors for real-time monitoring of fuel consumption, PTO torque and speed, trunk diameter and working time during the comminution of 61 poplar trees grown in a medium rotation coppice system. The data analysis was carried out on the entire dataset (about 29,000 records) without considering their belonging to different trees. By means of proper data ordinations, it has been possible to define all the intervals in which the chipping stopped (e.g., between two trees) and to exclude them from the intervals of actual chipping. This has allowed forcomputation of operative and actual working time, as well as of the basic power required to operate the chipper and the power for actual chipping. Subsequently, the parameter values observed during actual chipping were related to the cutting diameters measured at the same instant. Subsequently, the dataset was divided according to seven diameter classes, and, for each class, the descriptive statistical indices of working time, work productivity, CO2 emissions, energy requirement and fuel consumption were calculated. Eventually, the correlation between the variations in trunk diameter and other parameters was verified both on the whole dataset and based on the class average values. The analysis made it possible to identify the conditions of greatest efficiency for the chipper. More generally, the method could help to increase the accuracy of measurements aimed at characterizing the performance of chippers from the point of view of dynamic energy requirements as well as in relation to different wood species.

Uruguay propone un currículo competencial para la formación inicial de educadores en su nuevo plan de estudios. Se promueve en él una evaluación formativa, que priorice acciones educativas interdisciplinarias de las unidades curriculares que lo conforman, en pro del desarrollo de determinadas competencias. En esta experiencia educativa se integró el trabajo de enseñanza realizado en el trayecto de formación específico del primer año del Profesorado en Ciencias Biológicas con una evaluación formativa y sumativa de fin de curso, común a dos unidades curriculares. El dispositivo de evaluación implicó generar un producto didáctico y digital por parte de los profesores en formación, que fue analizado con el instrumento de la rúbrica. La metodología utilizada para evaluar la experiencia educativa fue mixta. En una primera fase se compararon los resultados de aprendizaje objetivados en la rúbrica aplicada en la evaluación formativa y sumativa; y en una segunda, se hizo un estudio del dispositivo evaluativo, a través de una encuesta valorativa global aplicada a los estudiantes sobre el cierre de los cursos. Los resultados muestran que los conceptos estructurantes enseñados a lo largo del año en las dos unidades curriculares de la formación de grado fueron utilizados por los profesores en formación para realizar una comparación de especies de organismos seleccionados, conforme a la consigna. Distintos aspectos en las dimensiones instrumentales y actitudinales de las competencias propuestas se pudieron evidenciar en la evaluación formativa y en la evaluación sumativa de cierre de cursos. Hay una valoración positiva de los estudiantes con respecto a la forma que se utilizó para evaluar de manera integral dos unidades curriculares específicas de la carrera.

ABSTRACT: Organic acids and botanicals have shown protective effects on gut barrier and against inflammation in broilers. However, their effects on intestinal digestive enzymes and nutrients transporters expression and functions have not been fully studied. The objective of this study was to understand how a microencapsulated blend of botanicals and organic acids affected intestinal enzyme activities and nutrient transporters expression and functions in broilers. A total of 288 birds were assigned to a commercial control diet or diet supplemented with 500 g/MT (metric ton) of the microencapsulated additive. Growth performance was recorded weekly. At d 21 and d 42, jejunum and ileum were isolated for enzyme (maltase, sucrase, and aminopeptidase) and transporter (SGLT1, GLUT2, GLUT1, EAAT3, B0AT1, and PepT1) analyses. Jejunum specific nutrients (glucose, alanine, and glutamate) transport activities were evaluated by Ussing chamber. Protein expression of nutrient transporters in small intestine were measured in mucosa and brush-border membrane (BBM) samples by western blot. Intestinal gene expression of the transporters was determined by RT-PCR. Statistical analysis was performed using Student's t-test comparing the supplemented diet to the control. The feed efficiency was significantly improved through the study period in the supplemented group (P ≤ 0.05). Significant changes of intestinal histology were shown in both jejunum (P ≤ 0.10) and ileum (P ≤ 0.05) after 21 d of treatment. At d21, jejunal maltase activity was upregulated (P ≤ 0.10). The Ussing chamber transport of glucose and alanine was increased, which was in line with increased gene expression (GLUT2, GLUT1, EAAT3, and B0AT1) (P ≤ 0.10 and P ≤ 0.05, respectively) and BBMV protein levels (B0AT1, P < 0.10). At d21, ileal sucrase and maltase activities were upregulated (P ≤ 0.05). Increased expressions of GLUT1, EAAT3, and B0AT1 were observed in both mRNA and protein levels (P ≤ 0.05). Similar pattern of changes was also shown at d42 of age. Our results suggest that feeding microencapsulated additives improves intestinal nutrient digestion and transporter expression and function in broilers, thereby enhancing feed efficiency.

Abstract Background During the COVID-19 pandemic, antigen diagnostic tests were frequently used for screening, triage, and diagnosis. Novel instrument-based antigen tests (iAg tests) hold the promise of outperforming their instrument-free, visually-read counterparts. Here, we provide a systematic review and meta-analysis of the SARS-CoV-2 iAg tests’ clinical accuracy. Methods We systematically searched MEDLINE (via PubMed), Web of Science, medRxiv, and bioRxiv for articles published before November 7th, 2022, evaluating the accuracy of iAg tests for SARS-CoV-2 detection. We performed a random effects meta-analysis to estimate sensitivity and specificity and used the QUADAS-2 tool to assess study quality and risk of bias. Sub-group analysis was conducted based on Ct value range, IFU-conformity, age, symptom presence and duration, and the variant of concern. Results We screened the titles and abstracts of 20,431 articles and included 114 publications that fulfilled the inclusion criteria. Additionally, we incorporated three articles sourced from the FIND website, totaling 117 studies encompassing 95,181 individuals, which evaluated the clinical accuracy of 24 commercial COVID-19 iAg tests. The studies varied in risk of bias but showed high applicability. Of 24 iAg tests from 99 studies assessed in the meta-analysis, the pooled sensitivity and specificity compared to molecular testing of a paired NP swab sample were 76.7% (95% CI 73.5 to 79.7) and 98.4% (95% CI 98.0 to 98.7), respectively. Higher sensitivity was noted in individuals with high viral load (99.6% [95% CI 96.8 to 100] at Ct-level ≤ 20) and within the first week of symptom onset (84.6% [95% CI 78.2 to 89.3]), but did not differ between tests conducted as per manufacturer’s instructions and those conducted differently, or between point-of-care and lab-based testing. Conclusion Overall, iAg tests have a high pooled specificity but a moderate pooled sensitivity, according to our analysis. The pooled sensitivity increases with lower Ct-values (a proxy for viral load), or within the first week of symptom onset, enabling reliable identification of most COVID-19 cases and highlighting the importance of context in test selection. The study underscores the need for careful evaluation considering performance variations and operational features of iAg tests.